This invention relates to guanidine compounds which selectively bind sigma brain receptors, to pharmaceutical compositions comprising them, to methods for determining in vitro the sigma brain receptor binding activity of organic compounds and to the use of compounds having such activity in the diagnosis and treatment of mental illness.
A wide variety of substituted guanidines are disclosed in the patent literature. See. e.g., U.S. Pat. Nos. 1,411,231; 1,422,506; 1,597,233; 1,642,180; 1,672,431; 1,730,388; 1,795,738; 1,850,682; 2,145,214; 2,254,009; 2,274,476; 2,289,543; 2,633,474; 3,117,994; 3,140,231; 3,159,676; 3,228,975; 3,248,426; 3,252,861; 3,270,054; 3,283,003; 3,301,755; 3,320,229; 3,409,669; 3,547,951; 3,639,477; 3,784,643; 3,804,898; 3,968,243; 3,975,533; 4,007,181; 4,051,256; 4,060,640; 4,109,014; 4,161,541; 4,169,154; 4,393,077; 4,471,137.
U.S. Pat. No. 3,547,951 discloses 1,3-dioxolan-4-yl-alkyl-substituted guanidines which have anti-hypertensive activity. Disclosed as a possible substituent on the other amino group is lower alkyl, including n-butyl. U.S. Pat. No. 3,248,426, describes (Example 5) a 1,3-disubstituted guanidine whose substituents are hydrophobic hydrocarbon groups, one of which is napthylmethyl and the other is n-butyl. U.S. Pat. No. 3,975,533 discloses o-halo-benzylideneamino-guanidines and their use as anti-depressants for overcoming psychic depression. U.S. Pat. No. 4,169,154 discloses the use of guanidines in the treatment of depression. U.S. Pat. No. 3,639,477 discloses propoxyguanidine compounds as having anorectic properties.
Three compounds which we found to possess selective sigma receptor binding activity are 1,3-di-phenylguanidine, 1,3-di-o-tolylguanidine and 1,3-dibutylguanidine.
Certain benzomorphan opiates, such as N-allylnormetazocine (SKF 10,047) and cyclazocine, in addition to analgesia, cause hallucinations, depersonalization, drunkenness and other psychotomimetic effects in man. In monkeys, dogs and rodents the psychotomimetic opiates cause behavioral and autonomic effects that are unlike those observed with administration of classical opiates such as morphine or the opioid peptides. Specific sigma "opioid" receptors in the brain are believed to mediate such atypical effects. Martin et al, (1976) J. Pharmacol. Exp. Ther. 197, 517-532. The sigma receptors are believed to also mediate the psychotomimetic effects of phencyclidine [PCP, angel dust], or alternatively, that psychotomimetic opiates act at specifc PCP receptors. Zukin, R. S. & Zukin, S. R., (1981) Mol. Pharmacol. 20, 246-254; Shannon, H. E., (1983) J. Pharmacol. Exp. Ther. 225, 144-152; White, J. M. & Holtzman, S. G., (1983) Psychopharmacology 80, 1-9; and Zukin et al., (1986) J. Neurochem. 46, 1032-1041. PCP is a drug of abuse that causes a behavorial syndrome in man similar to that which is observed in schizophrenic psychosis. Aniline, 0. & Pitts, F. N. Jr., (1982) CRC Critical Rev. Toxical. 10, 145-177. Because of the potent psychotomimetic effects of sigma opiates and PCP, it is believed that sigma (or PCP) receptors play a role in mental illness, particularly schizophrenia.
A systematic investigation of the role of sigma receptors in normal and abnormal brain function has been hindered by a lack of specific sigma receptor binding assays and bioassays. Development of such specific assays requires well-characterized, highly selective and potent sigma receptor ligands. Recent studies have shown that brain membrane receptors can be labeled in vitro with (.+-.)[.sup.3 H]SKF 10,047, Su, T. P., (1982) J. Pharmacol. Exp. Ther. 223, 284-290; (.+-.)[.sup.3 H]-Ethylketazocine, Tam, S. W., (1983) Proc. Natl. Acad, Sci. U.S.A. 80, 6703-6707; or with (.+-.)[.sup.3 H]SKF 10,047, Tam, S. W. & Cook, L. (1984) Proc. Natl. Acad. Sci. U.S.A. 81, 5618-56721; Martin, et al., (1984) J. Pharmacol. Exp. Ther. 231, 539-544; and Mickelson, M. M. & Lahti, R. A. (1985) Res. Commun. Chem. Pathol. Pharmacol. 47, 255,263 although not selectively, Gundlach et al., (1985) Eur. J. Pharmacol. 113, 465-466; and Largent B. L., Gundlach, A. L. & Snyder, S. H. (1986) J. Pharmacol. Exp. Ther., (In Press), and with (.+-. )[.sup.3 H]3-(3-hydroxyphenyl)N-(1-propyl)piperidine ((.+-.)[.sup.3 H]3-PPP), Largent et al., (1984) Proc. Natl. Acad. Sci. U.S.A. 81, 4983-4987, which is apparently more selective for sigma receptors than the others.
After the initial in vitro studies by Martin and collaborators (1976), Keats and Telford, Keats, A. S. and Telford, J., "Analgesics: Clinical Aspects" In: Molecular Modification in Drug Design, R. F. Gould, ed., Advances in Chemistry Series #45 Amer. Chem. Soc., Wash. D.C. (1964), and Haertzen, C. A. Cyclazocine and Nalorphine on the Addiction Research Center Inventory (ARCI), Psychopharmacologia (Berl.) 18, 366-377 (1970), numerous investigators set out to biochemically characterize the different opiate receptors (mu receptors, kappa receptors and sigma receptors) in vitro.
The first evidence for the existence of a separate sigma receptor in test tube experiments was provided by Su(1982) in a paper describing an etorphine-inaccesible binding site in guinea pig brain membranes which was apparently selectively labeled by tritium labeled SKF-10,047. To overcome the fact that SKF-10,047 could label multiple opioid receptors in the brain, Su performed his receptor binding assay using tritium labeled SKF-10,047 in the presence of excess unlabeled etorphine. Etorphine is a very strong opiate agonist drug which is known to bind to delta receptors, mu receptors and kappa receptors with almost equal potency. Su used etorphine to saturate all mu, kappa and delta receptors in a brain membrane preparation and then added tritium labeled SKF-10,047. This enabled him to detect a sigma binding site that was apparently different from mu, kappa and delta receptors.
A major breakthrough in identifying the sigma receptor as a separate entity occured when Tam et al., (1984) demonstrated that the previous problems in selectively labeling the sigma receptor were caused by the fact that in all previous experiments a racemic SKF-10,047 preparation was used. Tam showed that using a tritium labeled (+)-SKF-10,047 isomer he could selectively label a sigma receptor that was different from the mu, delta and kappa opioid receptors. On the other hand, Tam showed that (-)-SKF-10,047 apparently labeled the mu and kappa receptors but not the sigma receptors. Tam, S. W., Eur. J. Pharm. 109, 33-41 (1985). This finding has now been confirmed. (Martin et al, 1984). Moreover, there is evidence from behavorial experiments, Khazan et al., Neuropharm. 23, 983-987 (1984); Brady et al., Science 215, 178-180 (1981), that it is the (.+-.)-SKF-10,047 isomer that is solely responsible for the psychotomimetic effects of SKF-10,047.
One of the most important findings of the biochemical characterization of the sigma receptor has been that this receptor binds all synthetic opiate drugs that are known to have hallucinogenic and psychotomimetic effects. Opiates that do not have psychotomimetic effects in vivo do not bind to this receptor. Most importantly, it has been shown that besides hallucinogenic opiate drugs, the sigma receptor also binds many anti-psychotic drugs that are used clinically to treat hallucinations in schizophrenic patients. (Tam and Cook, 1984). The initial observations with regards to antipsychotic drug binding to the sigma receptor (Su, 1982) were subsequently extensively confirmed and extended by Tam and Cook (1984), who also showed that when one used radioactively labeled haloperidol, one of the most potent antipsychotic drugs that is used clinically, about half of the binding sites in brain membrane preparations are actually sigma receptors whereas the other half of the binding sites are apparently dopamine receptors. It has long been known that all antipsychotic drugs are also dopamine receptor antagonists and previously the beneficial actions of antipsychotic drugs in psychotic patients have been attributed to the dopamine receptor blocking effect of these drugs. It is clear from the work by Tam, however, showing that antipsychotic drugs bind also to the sigma receptor and from the behavorial work described above, that the actions of antipsychotic drugs on the sigma receptor may in one way or another cause the beneficial effects of alleviating hallucinations. Taken together all these observations make the sigma receptor a prime candidate to be involved in the pathogenesis of mental illness, particularly schizophrenia in which hallucinations are a major clinical symptom.
The antipsychotic and anti-schizophrenic drugs that are currently in use have very strong side effects that are mainly due to their action on dopamine receptors. The side effects often involve irreversible damage to the extrapyramidal nervous system which controls movement functions of the brain. Patients under long term anti-schizophrenic drug treatment often develop a syndrome that involves permanent damage of their ability to control coordinated movement.
We have identified a novel class of compounds which bind to the sigma receptor.
The foregoing studies have shown that the sigma binding site has the characteristics of (1) stereoselectivity towards dextrorotatory benzomorphan opiates and insensitivity for naloxone; (2) high affinity for haloperidol and moderate to high affinity for phenothiazine antipsychotic drugs which are also known to be potent dopamine receptor blockers; and (3) insensitivity for dopamine and apomorphine. This intriguing drug selectivity profile calls for a thorough analysis of the role of sigma receptors in normal and abnormal brain function. In order to do so, it is essential that a spectrum of highly selective and potent sigma receptor active compounds be available. This invention provides such compounds and wants to identify other drugs having such activity.